The immune system is able to detect the presence of infectious agents, and trigger a response against them, without destroying self tissues. This phenomenon is not trivial, given the enormous molecular diversity of pathogens, and their high replication and mutation rates. Multi-cellular organisms have been challenged over the course of evolution to develop several distinct immune-recognition systems, namely the ‘innate’ and ‘adaptive’ immune systems.
The evolutionarily ancient innate immune system detects the presence and nature of infection, provides the first line of host defense, and controls the initiation and determination of the effector class of the adaptive immune system.
Dendritic cells (DC) play an essential role in linking innate immunity and antigen-specific adaptive responses. To initiate an immune response, DC are primed (inter alia) by pathogen-associated molecular patterns (PAMP) expressed by pathogens. Then DC orchestrate development of the adaptive immune response, much more specialized and driven by antigen-specific T- and B-cells.
The antigen recognition and uptake functions of DC against pathogens are mediated by pattern recognition receptors (PRR) that discriminate among the PAMPs. These PRR expressed by DC include the Toll-like receptors (TLR)1. In addition, DC express another class of receptors, the C-type lectins, some of which may function as PRRs2-4, and/or mediate intercellular communication5-8. Within the C-type lectins, there is a group of type II proteins with a single extracellular C-type lectin domain (CTLD) that are structurally and evolutionary closely related, and clustered in the NK gene complex (NKC). Although these receptors lack a calcium binding site and a typical carbohydrate recognition domain, they may still be able to bind carbohydrates, as shown for Dectin-19. Some of these receptors (CD94/NKG2, NKG2D) interact with MHC-I or related molecules and either inhibit or activate NK and T cell cytotoxicity as a result of the balance between inhibitory and activating signals. However, for most of NK lectin receptors their binding specificity and relevance in NK or DC function is not known. Thus, C type lectins expressed on DC may act to recognise microbes, but may also regulate the communication of DC with other cells by recognizing specific cellular counterstructures.
The ontogeny and/or microenvironment in which DC are positioned may result in the expression of distinct combinations of surface receptors by DC. For example, phenotypic criteria alone allow the classification of mouse lymph node DCs into six main subpopulations10. Of these, conventional non-plasmacytoid DC in lymphoid tissues are traditionally sub-divided into CD8α− and CD8α+ subpopulations. It has been argued that different DC subsets may be involved in specific recognition of certain pathogens and/or regulate different immune responses, e.g. Th1 or Th2 (immunity) or regulatory T cells (tolerance)11. However, the phenotype and functional behavior of DCs is also significantly conditioned by external activating stimuli, denoting significant plasticity. As a first approach to understanding the differences between DC subsets, DC subpopulations were isolated and their properties in vitro were assessed: in mouse, CD8α+ and CD8α− subsets of spleen DC differ in their ability to make IL-12 in vitro12,13. However, the differential IL-12 production in vitro was also determined by the pattern recognition, demonstrating functional flexibility of different DC subsets14. As a second approach, DC subsets were isolated, antigen-pulsed, and then re-infused in vivo. CD8α+ and CD8α− subsets differentially primed Th1 and Th2 responses in vivo15,16. Immune therapy is feasible if we can determine molecules that are selectively expressed in a particular DC subset. These molecules can then be targeted to alter the function of this subset of DCs.